Un fisiólogo respiratorio: sea como sea / A Respiratory Physiologist: by Hook or by Crook

La Revista Am J Respir Care Crit Care Med, también conocida como "Blue Journal", es una publicación mensual de American Thoracic Society. Desde hace años publica periódicamente una "viñeta" titulada: Como realmente ocurrió. Durante el año 2003, Joseph Milic-Emili relató cómo se transformó en fisiólogo de la mecánica respiratoria

Impact of hemodialysis on dyspnea and lung function in end stage kidney disease patients.

BACKGROUND: Respiratory symptoms are usually underestimated in patients with chronic kidney disease undergoing maintenance hemodialysis. Therefore, we set out to investigate the prevalence of patients chronic dyspnea and the relationship of the symptom to lung function indices. METHODS: Twenty-five clinically stable hemodialysis patients were included. The mMRC dyspnea scale was applied before and after hemodialysis. Spirometry, single breath nitrogen test, arterial blood gases, static maximum inspiratory (P(imax)) and expiratory (P(emax)) muscle pressures, and mouth occlusion pressure (P 0.1) were also measured. RESULTS: Despite normal spirometry, all patients (100%) reported mild to moderate degree of chronic dyspnea pre which was reduced after hemodialysis. The sole predictor of (Δ) mMRC was the (Δ) P 0.1 (r = 0.71, P < 0.001). The P(imax) was reduced before and correlated with the duration of hemodialysis (r = 0.614, P < 0.001), whilst after the session it was significantly increased (P < 0.001). Finally (Δ) weight was correlated with the (Δ) P(imax) %pred (r = 0.533, P = 0,006) and with the (Δ) CV (%pred) (r = 0.65, P < 0.001). CONCLUSION: We conclude that dyspnea is the major symptom among the CKD patients that improves after hemodialysis. The neuromechanical dissociation observed probably is one of the major pathophysiologic mechanisms of dyspnea.

Recumbent deoxygenation in mild/moderate liver cirrhosis: the "clinodeoxia". The ortho-clino paradigm.

BACKGROUND: While the effects of postural change on arterial oxygenation have been well documented in normal subjects, and attributed to the relationship of closing volume (CV) to the tidal volume, in liver cirrhosis such postural changes have been evaluated mainly in a rare, peculiar clinical end-stage condition which is characterized by increased dyspnea shifting from supine to upright position ("platypnea"). The latter is associated with worsening of PaO2 ("orthodeoxia"). We evaluated the effects of postural changes on arterial oxygenation in patients affected by mild/moderate liver cirrhosis. METHODS: We performed pulmonary function tests and arterial blood gas evaluation in sitting and supine positions in 22 patients with mild/moderate liver cirrhosis, biopsy-proved, and 22 matched non-smokers control subjects. RESULTS: Recumbency elicited a decrease of PaO2 (Δ(sup-sit)PaO2) in 19 out of 22 controls and in all but one cirrhotics. The magnitude of this postural change was significantly (p = 0.04) greater in cirrhotics (9.6 ± 5.3%) compared to controls (6.7 ± 3.7%). In the subset of cirrhotics younger than 60 yrs and with PaO2 greater than 80 mmHg in sitting position, the Δ(sup-sit)PaO2 in recumbency further increased to 12 ± 5.8%, significantly (p = 0.014) greater than in same subgroup of controls (7.1 ± 3.8%). CONCLUSIONS: In mild/moderate liver cirrhosis the postural variations in PaO2 follow the normal trends, but are of greater magnitude probably as a consequence of hypoventilated units of lung for postural and disease-linked tidal airway closure, resulting in more pronounced recumbent hypoxemia ("clinodeoxia").

Dyspnea and respiratory muscle strength in end-stage liver disease.

AIM: To investigate the prevalence of chronic dyspnea and its relationship to respiratory muscle function in end-stage liver disease. METHODS: Sixty-eight consecutive, ambulatory, Caucasian patients with end-stage liver disease, candidates for liver transplantation, were referred for preoperative respiratory function assessment. Forty of these (29 men) were included in this preliminary study after applying strict inclusion and exclusion criteria. Seventeen of 40 patients (42%) had ascites, but none of them was cachectic. Fifteen of 40 patients (38%) had a history of hepatic encephalopathy, though none of them was symptomatic at study time. All patients with a known history and/or presence of co-morbidities were excluded. Chronic dyspnea was rated according to the modified medical research council (mMRC) 6-point scale. Liver disease severity was assessed according to the Model for end-stage liver disease (MELD). Routine lung function tests, maximum static expiratory (Pemax) and inspiratory (Pimax) mouth pressures were measured. Respiratory muscle strength (RMS) was calculated from Pimax and Pemax values. In addition, arterial blood gases and pattern of breathing (VE: minute ventilation; VT: tidal volume; VT/TI: mean inspiratory flow; TI: duration of inspiration) were measured. RESULTS: Thirty-five (88%) of 40 patients aged (mean ± SD) 52 ± 10 years reported various degrees of chronic dyspnea (mMRC), ranging from 0 to 4, with a mean value of 2.0 ± 1.2. MELD score was 14 ± 6. Pemax, percent of predicted (%pred) was 105 ± 35, Pimax, %pred was 90 ± 29, and RMS, %pred was 97 ± 30. These pressures were below the normal limits in 12 (30%), 15 (38%), and 14 (35%) patients, respectively. Furthermore, comparing the subgroups of ascites to non-ascites patients, all respiratory muscle indices measured were found significantly decreased in ascites patients. Patients with ascites also had a significantly worse MELD score compared to non-ascites ones (P = 0.006). Significant correlations were found between chronic dyspnea and respiratory muscle function indices in all patients. Specifically, mMRC score was significantly correlated with Pemax, Pimax, and RMS (r = -0.53, P < 0.001; r = -0.42, P < 0.01; r = -0.51, P < 0.001, respectively). These correlations were substantially closer in the non-ascites subgroup (r = -0.82, P < 0.0001; r = -0.61, P < 0.01; r = -0.79, P < 0.0001, respectively) compared to all patients. Similar results were found for the relationship between mMRC vs MELD score, and MELD score vs respiratory muscle strength indices. In all patients the sole predictor of mMRC score was RMS (r = -0.51, P < 0.001). In the subgroup of patients without ascites this relationship becomes closer (r = -0.79, P < 0.001), whilst this relationship breaks down in the subgroup of patients with ascites. The disappearance of such a correlation may be due to the fact that ascites acts as a "confounding" factor. PaCO2 (4.4 ± 0.5 kPa) was increased, whereas pH (7.49 ± 0.04) was decreased in 26 (65%) and 34 (85%) patients, respectively. PaO2 (12.3 ± 0.04 kPa) was within normal limits. VE (11.5 ± 3.5 L/min), VT (0.735 ± 0.287 L), and VT/TI (0.449±0.129 L/s) were increased signifying hyperventilation in both subgroups of patients. VT/TI was significantly higher in patients with ascites than without ascites. Significant correlations, albeit weak, were found for PaCO2 with VE and VT/TI (r = -0.44, P < 0.01; r = -0.41, P < 0.01, respectively). CONCLUSION: The prevalence of chronic dyspnea is 88% in end-stage liver disease. The mMRC score closely correlates with respiratory muscle strength.

Pulmonary function and expiratory flow limitation in acute cervical spinal cord injury.

OBJECTIVE: To identify the nature of the changes of respiratory mechanics in patients with middle cervical spinal cord injury (SCI) and their correlation with posture. DESIGN: Clinical trial. SETTING: Acute SCI unit. PARTICIPANTS: Patients with SCI (N=34) at C4-5 level studied within 6 months of injury. INTERVENTIONS: Patients were assessed by the negative expiratory pressure test, maximal static respiratory pressure test, and standard spirometry. MAIN OUTCOME MEASURES: The following respiratory variables were recorded in both the semirecumbent and supine positions: (1) tidal expiratory flow limitation (TEFL); (2) airway resistances; (3) mouth occlusion pressure developed 0.1 seconds after occluded inspiration at functional residual capacity (P(0.1)); (4) maximal static inspiratory pressure (MIP) and maximal static expiratory pressure (MEP); and (5) spirometric data. RESULTS: TEFL was detected in 32% of the patients in the supine position and in 9% in the semirecumbent position. Airway resistances and P(0.1) were much higher compared with normative values, while MIP and MEP were markedly reduced. The ratio of forced expiratory volume in 1 second to forced vital capacity was less than 70%, while the other spirometric data were reduced up to 30% of predicted values. CONCLUSIONS: Patients with middle cervical SCI can develop TEFL. The presence of TEFL, associated with increased airway resistance, could increase the work of breathing in the presence of a reduced capacity of the respiratory muscles to respond to the increased load. The semirecumbent position and the use of continuous positive airway pressure can be helpful to (1) reduce the extent of TEFL and avoid the opening/closure of the small airways; (2) decrease airway resistance; and (3) maintain the expiratory flow as high as possible, which aids in the removal of secretions.

MRC chronic Dyspnea Scale: Relationships with cardiopulmonary exercise testing and 6-minute walk test in idiopathic pulmonary fibrosis patients: a prospective study.

BACKGROUND: Exertional dyspnea is the most prominent and disabling feature in idiopathic pulmonary fibrosis (IPF). The Medical Research Chronic (MRC) chronic dyspnea score as well as physiological measurements obtained during cardiopulmonary exercise testing (CPET) and the 6-minute walk test (6MWT) are shown to provide information on the severity and survival of disease. METHODS: We prospectively recruited IPF patients and examined the relationship between the MRC score and either CPET or 6MWT parameters known to reflect physiologic derangements limiting exercise capacity in IPF patients RESULTS: Twenty-five patients with IPF were included in the study. Significant correlations were found between the MRC score and the distance (r = -.781, p < 0.001), the SPO2 at the initiation and the end (r = -.542, p = 0.005 and r = -.713, p < 0.001 respectively) and the desaturation index (r = .634, p = 0.001) for the 6MWT; the MRC score and VO2 peak/kg (r = -.731, p < 0.001), SPO2 at peak exercise (r = -. 682, p < 0.001), VE/VCO2 slope (r = .731, p < 0.001), VE/VCO2 at AT (r = .630, p = 0.002) and the Borg scale at peak exercise (r = .50, p = 0.01) for the CPET. In multiple logistic regression analysis, the only variable independently related to the MRC is the distance walked at the 6MWT. CONCLUSION: In this population of IPF patients a good correlation was found between the MRC chronic dyspnoea score and physiological parameters obtained during maximal and submaximal exercise testing known to reflect ventilatory impairment and exercise limitation as well as disease severity and survival. This finding is described for the first time in the literature in this group of patients as far as we know and could explain why a simple chronic dyspnea score provides reliable prognostic information on IPF.

The effect of lung expansion and positive end-expiratory pressure on respiratory mechanics in anesthetized children.

BACKGROUND: Imaging studies have shown that general anesthesia in children results in atelectasis. Lung recruitment total lung capacity (TLC) maneuvers plus positive end-expiratory pressure (PEEP) are effective in preventing atelectasis. However, physiological changes in children during general anesthesia have not been elucidated. METHODS: In eight anesthetized and mechanically ventilated children (median age: 3.5 years; range: 2.3-6.5), we measured static respiratory system elastance (E(st)), flow resistance (R(int)), and elastance and resistance components resulting from tissue viscoelasticity (deltaE and deltaR, respectively) using the constant inflow, end-inspiratory occlusion method preceded by TLC maneuvers, both with zero PEEP (ZEEP) and PEEP (5 cm H2O) for comparison. RESULTS: With constant inspiratory flow V(I) and ZEEP, increases in end-inspiratory lung volume above relaxation volume (tidal volume, V(T)) from 8 to 20 mL x kg(-1) resulted in decreases in E(st) from 1.06 to 0.82 cm H2O x mL(-1) x kg, deltaE from 0.16 to 0.09, and R(int) from 0.13 to 0.11 cm H2O x mL(-1) x s x kg, whereas deltaR increased from 0.08 to 0.12 (P < 0.05). Similar relationships were found with PEEP. Increases in V(I) (8 to 26 mL x s(-1) x kg) with constant V(T) and ZEEP resulted in decreases in E(st) from 1.09 to 0.9 and deltaR from 0.17 to 0.06 (P < 0.01), whereas deltaE and R(int) did not change. There was a similar flow and volume dependence of elastance and resistance with PEEP. CONCLUSIONS: The observed steady decreases in E(st) with increasing V(T) (up to 16 mL/kg with PEEP) indicate marked reductions in end-expiratory relaxation volume (functional residual capacity) even with PEEP. Similarity in results with ZEEP and PEEP suggests that TLC-maneuvers and O2-N2 ventilation prevented airway closure throughout the study.

CD8+ T lymphocytes in bronchoalveolar lavage in idiopathic pulmonary fibrosis.

BACKGROUND: Recently it was shown that in Idiopathic Pulmonary Fibrosis (IPF) tissue infiltrating CD8+ T lymphocytes (TLs) are associated with breathlessness and physiological indices of disease severity, as well as that CD8+ TLs recovered by bronchoalveolar lavage (BAL) relate to those infiltrating lung tissue. Since BAL is a far less invasive technique than tissue biopsy to study mechanisms in IPF we further investigated the usefulness offered by this means by studying the relationship between BAL macrophages, neutrophils, eosinophils, CD3+, CD4+, CD8+, CD8+/38+ TLs and CD4+/CD8+ ratio with breathlessness and physiological indices. PATIENTS AND METHODS: 27 IPF patients, 63 +/- 9 years of age were examined. Cell counts were expressed as percentages of total cells and TLs were evaluated by flow cytometry. FEV1, FVC, TLC, RV, DLCO, PaO2, and PaCO2 were measured in all. Breathlessness was assessed by the Medical Research Council (MRC) chronic dyspnoea scale. RESULTS: CD8+ TLs correlated positively (rs = 0.46, p = 0.02), while CD4+/CD8+ ratio negatively (rs = -0.54, p = 0.006) with the MRC grade. CD8+ TLs correlated negatively with RV (rs = -0.50, p = 0.017). CD8+/38+ TLs were negatively related to the FEV1 and FVC (rs = -0.53, p = 0.03 and rs = -0.59, p = 0.02, respectively). Neutrophils correlated positively with the MRC grade (rs = 0.42, p = 0.03), and negatively with the DLCO (rs = -0.54, p = 0.005), PaO2 (rs = -0.44, p = 0.03), and PaCO2 (rs = -0.52, p = 0.01). CONCLUSION: BAL CD8+ TLs associations with physiological and clinical indices seem to indicate their implication in IPF pathogenesis, confirming our previous tissue study.

Closing volume: a reappraisal (1967-2007).

Measurement of closing volume (CV) allows detection of presence or absence of tidal airway closure, i.e. cyclic opening and closure of peripheral airways with concurrent (1) inhomogeneity of distribution of ventilation and impaired gas exchange; and (2) risk of peripheral airway injury. Tidal airway closure, which can occur when the CV exceeds the end-expiratory lung volume (EELV), is commonly observed in diseases characterised by increased CV (e.g. chronic obstructive pulmonary disease, asthma) and/or decreased EELV (e.g. obesity, chronic heart failure). Risk of tidal airway closure is enhanced by ageing. In patients with tidal airway closure (CV > EELV) there is not only impairment of pulmonary gas exchange, but also peripheral airway disease due to injury of the peripheral airways. In view of this, the causes and consequences of tidal airway closure are reviewed, and further studies are suggested. In addition, assessment of the "open volume", as opposed to the "closing volume", is proposed because it is easier to perform and it requires less equipment.

Different angiogenic activity in pulmonary sarcoidosis and idiopathic pulmonary fibrosis.

BACKGROUND: Recent evidence has shown that several chemokines--including those involved in angiogenesis--have been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and sarcoidosis. We speculated that these differences could be attributed to distinct angiogenic and angiostatic profiles. This hypothesis was investigated by estimating the levels of three angiogenic chemokines (growth-related gene [GRO]-alpha, epithelial neutrophil-activating protein [ENA]-78, and interleukin [IL]-8), and three angiostatic chemokines (monokine induced by interferon (IFN)-gamma [MIG], IFN-gamma-inducible protein [IP]-10, and IFN-gamma-inducible T-cell alpha chemoattractant) in serum and BAL fluid (BALF). METHODS: We studied prospectively 20 patients with sarcoidosis (median age, 46 years; range, 25 to 65 years), 20 patients with IPF (median age, 68 years; range, 40 to 75 years), and 10 normal subjects (median age, 39 years; range, 26 to 60 years). RESULTS: The GRO-a serum and BALF levels of IPF patients were found significantly increased in comparison with healthy subjects (799 pg/mL vs 294 pg/mL [p = 0.022] and 1,827 pg/mL vs 94 pg/mL [p < 0.001], respectively) and sarcoidosis patients (799 pg/mL vs 44 pg/mL [p < 0.001] and 1,827 pg/mL vs 214 pg/mL [p < 0.001], respectively). Moreover, ENA-78 and IL-8 BALF levels in IPF patients were significantly higher compared with sarcoidosis patients (191 pg/mL vs 30 pg/mL [p < 0.001] and 640 pg/mL vs 94 pg/mL [p = 0.03], respectively). MIG serum levels in IPF patients were found significantly upregulated in comparison with sarcoidosis patients and healthy control subjects. However, MIG and IP-10 BALF levels (1,136 pg/mL vs 66 pg/mL [p < 0.001] and 112 pg/mL vs 56 pg/mL [p = 0.037], respectively) were significantly higher in sarcoidosis patients compared with IPF patients. CONCLUSIONS: Our data suggest distinct angiogenic profiles between IPF and sarcoidosis, indicating a potential different role of CXC chemokines in the local immunologic response in IPF and pulmonary sarcoidosis.

Orthopnea and tidal expiratory flow limitation in chronic heart failure.

BACKGROUND: Tidal expiratory flow limitation (FL) is common in patients with acute left heart failure and contributes significantly to orthopnea. Whether tidal FL exists in patients with chronic heart failure (CHF) remains to be determined. PURPOSES: To measure tidal FL and respiratory function in CHF patients and their relationships to orthopnea. METHODS: In 20 CHF patients (mean [+/- SD] ejection fraction, 23 +/- 8%; mean systolic pulmonary artery pressure [sPAP], 46 +/- 18 mm Hg; mean age, 59 +/- 11 years) and 20 control subjects who were matched for age and gender, we assessed FL, Borg score, spirometry, maximal inspiratory pressure (Pimax), mouth occlusion pressure 100 ms after the onset of inspiratory effort (P(0.1)), and breathing pattern in both the sitting and supine positions. The Medical Research Council score and orthopnea score were also determined. RESULTS: In the sitting position, tidal FL was absent in all patients and healthy subjects. In CHF patients, Pimax was reduced, and ventilation and P(0.1)/Pimax ratio was increased relative to those of control subjects. In the supine position, 12 CHF patients had FL and 18 CHF patients claimed orthopnea with a mean Borg score increasing from 0.5 +/- 0.7 in the sitting position to 2.7 +/- 1.5 in the supine position in CHF patients. In contrast, orthopnea was absent in all control subjects. The FL patients were older than the non-FL patients (mean age, 63 +/- 8 vs 53 +/- 12 years, respectively; p < 0.03). In shifting from the seated to the supine position, the P(0.1)/Pimax ratio and the effective inspiratory impedance increased more in CHF patients than in control subjects. The best predictors of orthopnea in CHF patients were sPAP, supine Pimax, and the percentage change in inspiratory capacity (IC) from the seated to the supine position (r(2) = 0.64; p < 0.001). CONCLUSIONS: In sitting CHF patients, tidal FL is absent but is common supine. Supine FL, together with increased respiratory impedance and decreased inspiratory muscle force, can elicit orthopnea, whom independent indicators are sPAP, supine Pimax and change in IC percentage.

Closing capacity and gas exchange in chronic heart failure.

BACKGROUND: Although it is commonly assumed that pulmonary congestion and edema in patients with chronic heart failure (CHF) promotes peripheral airway closure, closing capacity (CC) has not been measured in CHF patients. PURPOSES: To measure CC and the presence or absence of airway closure and expiratory flow limitation (FL) during resting breathing in CHF patients. METHODS: In 20 CHF patients and 20 control subjects, we assessed CC, FL, spirometry, blood gas levels, control of breathing, breathing pattern, and dyspnea. RESULTS: The patients exhibited a mild restrictive pattern, but the CC was not significantly different from that in control subjects. Nevertheless, airway closure during tidal breathing (ie, CC greater than functional residual capacity [FRC]) was present in most patients but was absent in all control subjects. As a result of the maldistribution of ventilation and the concurrent impairment of gas exchange, the mean (+/- SD) alveolar-arterial oxygen pressure difference increased significantly in CHF patients (4.3 +/- 1.2 vs 2.7 +/- 0.5 kPa, respectively; p < 0.001) and correlated with systolic pulmonary artery pressure (r = 0.49; p < 0.03). Tidal FL is absent in CHF patients. Mouth occlusion pressure 100 ms after onset of inspiratory effort (P0.1) as a percentage of maximal inspiratory pressure (Pimax) together with ventilation were increased in CHF patients (p < 0.01 and p < 0.005, respectively). The increase in ventilation was due entirely to increased respiratory frequency (fR) with a concurrent decrease in Paco2. Chronic dyspnea (scored with the Medical Research Council [MRC] scale) correlated (r2= 0.61; p < 0.001) with fR and P0.1/Pimax. CONCLUSIONS: In CHF patients at rest, CC is not increased, but, as a result of decreased FRC, airway closure during tidal breathing is present, promoting the maldistribution of ventilation, ventilation-perfusion mismatch, and impaired gas exchange. The ventilation is increased as result of increased fR, and Pimax is decreased with a concurrent increase in P0.1, implying that there is a proportionately greater inspiratory effort per breath (P0.1/Pimax). These, together with the increased fR, are the only significant contributors to increases in the MRC dyspnea score.

CD8+ T lymphocytes in lung tissue from patients with idiopathic pulmonary fibrosis.

BACKGROUND: Several studies have implicated a role of inflammation in the pathogenesis of lung damage in idiopathic pulmonary fibrosis (IPF). Parenchymal lung damage leads to defects in mechanics and gas exchange and clinically manifests with exertional dyspnea. Investigations of inflammatory cells in IPF have shown that eosinophils, neutrophils and CD8+ TLs may be associated with worse prognosis. We wished to investigate by quantitative immunohistochemistry infiltrating macrophages, neutrophils and T lymphocytes (TLs) subpopulations (CD3+, CD4+ and CD8+) in lung tissue of patients with IPF and their correlation with lung function indices and grade of dyspnoea. METHODS: Surgical biopsies of 12 patients with IPF were immunohistochemically stained with mouse monoclonal antibodies (anti-CD68 for macrophages, anti-elastase for neutrophils, and anti-CD3, anti-CD4, anti-CD8 for CD3+TLs, CD4+TLs, and CD8+TLs respectively). The number of positively stained cells was determined by observer-interactive computerized image analysis (SAMBA microscopic image processor). Cell numbers were expressed in percentage of immunopositive nuclear surface in relation to the total nuclear surface of infiltrative cells within the tissue (labeling Index). Correlations were performed between cell numbers and physiological indices [FEV1, FVC, TLC, DLCO, PaO2, PaCO2 and P(A-a)O2)] as well as dyspnoea scores assessed by the Medical Research Council (MRC) scale. RESULTS: Elastase positive cells accounted for the 7.04% +/- 1.1 of total cells, CD68+ cells for the 16.6% +/- 2, CD3+ TLs for the 28.8% +/- 7, CD4+ TLs for the 14.5 +/- 4 and CD8+ TLs for the 13.8 +/- 4. CD8+TLs correlated inversely with FVC % predicted (rs = -0.67, p = 0.01), TLC % predicted (rs = -0.68, p = 0.01), DLCO % predicted (rs = -0.61, p = 0.04), and PaO2 (rs = -0.60, p = 0.04). Positive correlations were found between CD8+TLs and P(A-a)O2 (rs = 0.65, p = 0.02) and CD8+TLs and MRC score (rs = 0.63, p = 0.02). Additionally, CD68+ cells presented negative correlations with both FVC % predicted (rs = -0.80, p = 0.002) and FEV1 % predicted (rs = -0.68, p = 0.01). CONCLUSION: In UIP/IPF tissue infiltrating mononuclear cells and especially CD8+ TLs are associated with the grade of dyspnoea and functional parameters of disease severity implicating that they might play a role in its pathogenesis.

The Medical Research Council dyspnea scale in the estimation of disease severity in idiopathic pulmonary fibrosis.

BACKGROUND: Medical Research Council (MRC) chronic dyspnea scale, used for the estimation of disability due to dyspnea, may serve as a simple index of disease severity and extent in patients with idiopathic pulmonary fibrosis (IPF). However, its relationship with other commonly used measures has not been evaluated. METHODS: The association of MRC chronic dyspnea scale with lung function indices and high-resolution computerized tomography (HRCT) scores such as the total interstitial disease score (TIDs) and the fibrosis score (Fs) was examined in 26 untreated patients with IPF sequentially recruited over a period of 3 years. The aim of this observational study was to explore the relationship between dyspnea, impairment of lung function and CT estimation of disease severity in patients with IPF. RESULTS: The MRC dyspnea score was significantly associated with FVC, FEV1, TLC, DLCO, PaO2, and PaCO2 and with both HRCT scores. In multiple regression analysis only the FVC (OR = 0.85, 95% CI = 0.75-0.95, P = 0.004) and PaCO2 (OR = 0.69, 95% CI = 0.50-0.95, P = 0.02) correlated with dyspnea. Furthermore, both TIDs and Fs were negatively associated with FVC, FEV1, TLC and PaO2. In multiple regression analysis only the FVC correlated with both TIDs (r2 = 0.57, P = 0.0001) and Fs (r2 = 0.46, P = 0.0005). CONCLUSIONS: These observations suggest that the MRC dyspnea scale could offer useful information about the estimation of severity in patients with IPF. Furthermore among functional indices the FVC seems to be the best estimator of disease severity and extent.

Effects of mechanical ventilation at low lung volume on respiratory mechanics and nitric oxide exhalation in normal rabbits.

Lung mechanics, exhaled NO (NOe), and TNF-alpha in serum and bronchoalveolar lavage fluid were assessed in eight closed and eight open chest, normal anesthetized rabbits undergoing prolonged (3-4 h) mechanical ventilation (MV) at low volume with physiological tidal volumes (10 ml/kg). Relative to initial MV on positive end-expiratory pressure (PEEP), MV at low volume increased lung quasi-static elastance (+267 and +281%), airway (+471 and +382%) and viscolelastic resistance (+480 and +294%), and decreased NOe (-42 and -25%) in closed and open chest rabbits, respectively. After restoration of PEEP, viscoelastic resistance returned to control, whereas airway resistance remained elevated (+120 and +31%) and NOe low (-25 and -20%) in both groups of rabbits. Elastance remained elevated (+23%) only in closed-chest animals, being associated with interstitial pulmonary edema, as reflected by increased lung wet-to-dry weight ratio with normal albumin concentration in bronchoalveolar lavage fluid. In contrast, in 16 additional closed- and open-chest rabbits, there were no changes of lung mechanics or NOe after prolonged MV on PEEP only. At the end of prolonged MV, TNF-alpha was practically undetectable in serum, whereas its concentration in bronchoalveolar lavage fluid was low and similar in animals subjected or not subjected to ventilation at low volume (62 vs. 43 pg/ml). These results indicate that mechanical injury of peripheral airways due to their cyclic opening and closing during ventilation at low volume results in changes in lung mechanics and reduction in NOe and that these alterations are not mediated by a proinflammatory process, since this is expressed by TNF-alpha levels.

Effect of heliox breathing on dynamic hyperinflation in COPD patients.

BACKGROUND: and objective: Patients with COPD exhibit increased inspiratory work and dyspnea due to dynamic hyperinflation caused by expiratory flow limitation. Helium-oxygen mixtures (ie, heliox) have been used in treating these patients on the assumption that, by lowering airway resistance, they might be beneficial. METHODS: In 22 patients with COPD, the presence of expiratory flow limitation was assessed with patients in the sitting and supine positions using the negative expiratory pressure technique, and the effects of heliox (80% He, 20% O2) on breathing pattern, expiratory flow limitation, and dynamic hyperinflation, evaluated from the change in inspiratory capacity (IC), were measured at rest and were compared with those due to inhaled salbutamol. RESULTS: During air breathing, 13 patients experienced flow limitation while in the sitting position and 18 experienced flow limitation while in the supine position. Neither heliox nor salbutamol therapy changed the breathing pattern in any of the patients, regardless of posture and the presence or absence of expiratory flow limitation. However, in both positions IC increased significantly in most flow-limited patients after bronchodilator administration, but not after heliox administration. CONCLUSIONS: Since heliox had no effect on dynamic hyperinflation, the use of this gas mixture, which is costly and cumbersome, does not appear to be beneficial in stable patients with COPD breathing at rest.

Dependence of lung injury on inflation rate during low-volume ventilation in normal open-chest rabbits.

Lung mechanics and morphometry were assessed in two groups of nine normal open-chest rabbits mechanically ventilated (MV) for 3-4 h at zero end-expiratory pressure (ZEEP) with physiological tidal volumes (Vt; 11 ml/kg) and high (group A) or low (group B) inflation flow (44 and 6.1 ml x kg(-1) x s(-1), respectively). Relative to initial MV on positive end-expiratory pressure (PEEP; 2.3 cmH(2)O), MV on ZEEP increased quasi-static elastance and airway and viscoelastic resistance more in group A (+251, +393, and +225%, respectively) than in group B (+180, +247, and +183%, respectively), with no change in viscoelastic time constant. After restoration of PEEP, quasi-static elastance and viscoelastic resistance returned to control, whereas airway resistance, still relative to initial values, remained elevated more in group A (+86%) than in group B (+33%). In contrast, prolonged high-flow MV on PEEP had no effect on lung mechanics of seven open-chest rabbits (group C). Gas exchange on PEEP was equally preserved in all groups, and the lung wet-to-dry ratios were normal. Relative to group C, both groups A and B had an increased percentage of abnormal alveolar-bronchiolar attachments and number of polymorphonuclear leukocytes in alveolar septa, the latter being significantly larger in group A than in group B. Thus prolonged MV on ZEEP with cyclic opening-closing of peripheral airways causes alveolar-bronchiolar uncoupling and parenchymal inflammation with concurrent, persistent increase in airway resistance, which are worsened by high-inflation flow.

Extrathoracic expiratory flow limitation in obesity and obstructive and restrictive disorders: effects of increasing negative expiratory pressure.

BACKGROUND: The negative expiratory pressure (NEP) technique is used to detect intrathoracic expiratory flow limitation (EFL) in patients with respiratory disorders. Application of NEP may result in a sustained decrease of flow below control as a result of upper airway collapse, which may invalidate interpretation of the test. This response to NEP is common in patients with obstructive sleep apnea syndrome (OSAS). The prevalence of this phenomenon, however, has not been studied in healthy subjects and patients with obstructive and restrictive disorders without OSAS. PURPOSE: The purpose of this study was as follows: (1) to assess the effects of increasing NEP levels on upper airway patency, and (2) to determine the factors that predispose to intrathoracic flow limitation or upper airway collapse during NEP application in different postures in healthy nonobese and obese subjects, and in patients with obstructive and restrictive respiratory disorders. SUBJECTS: Fifty-six patients with obstructive airway disease (21 patients with COPD, 16 patients with simple chronic bronchitis, and 19 patients with asthma) were compared with 47 patients with restrictive respiratory disorders, 20 nonobese and healthy subjects, and 9 obese subjects (body mass index > 30) without a history of snoring or OSAS. METHODS: NEP at levels of 5 cm H(2)O, 10 cm H(2)O, and 15 cm H(2)O were applied at the mouth immediately after the onset of tidal expiration while seated and supine. Intrathoracic EFL was defined as no change in expiratory flow over any portion of the immediately preceding control breath. Upper airway collapse or narrowing was detected when flows decreased below those of the control breath. RESULTS: Ten patients (18%) with obstructive airway disease (7 patients with COPD) exhibited EFL at NEP of 5 cm H(2)O (4 patients were supine only, and 6 patients were both supine and sitting). No patient with restrictive disorders or healthy obese and nonobese subjects presented EFL at NEP of 5 cm H(2)O. In almost all subgroups, both seated and supine, subjects exhibited a transient decrease of flow below control immediately after the application of NEP in occasional breaths. As NEP increased, the number of subjects who exhibited this response in occasional breaths declined, while the number of subjects who displayed this pattern in all breaths increased. Conversely, there were very few subjects in each subgroup who exhibited a sustained decrease in flow below control in occasional breaths at NEP at 5 cm H(2)O, and only one healthy obese subject who displayed this response in all breaths in supine position only. CONCLUSIONS: In general, an increase in NEP resulted in only rare instances of sustained decrease in flow below control in all breaths. While transient decreases in flow exhibited immediately after the onset of NEP in all breaths are common and become more prevalent as NEP is increased beyond 5 cm H(2)O, there are only rare instances of sustained decrease in flow below control throughout expiration at all levels of NEP tested, indicating an appropriate upper airway dilator response that maintains patency. Thus, in subjects without OSAS, assessment of intrathoracic EFL with NEP is valid in almost all instances.

Does mechanical injury of the peripheral airways play a role in the genesis of COPD in smokers?

In the present account it is proposed that in smokers the transition from peripheral airway disease to COPD is characterized by three sequential stages: Stage I, during which the closing volume eventually exceeds the functional residual capacity; Stage II, during which tidal expiratory flow limitation (EFL) is eventually exhibited; and Stage III, during which dynamic hyperinflation progressively increases leading to dyspnea and exercise limitation, which may be considered as markers of overt disease. Presence of airway closure (Stage I) and EFL (Stage II) in the tidal volume range may promote peripheral airway injury and accelerate the abnormalities of lung function. It is such injury that may determine which smoker is destined to develop COPD.

Orthopnea and tidal expiratory flow limitation in patients with euthyroid goiter.

BACKGROUND: Nontoxic goiters can cause extrathoracic upper airway obstruction and, if large, may extend into the thorax, causing intrathoracic airway obstruction. Although patients with goiter often report orthopnea, there are few studies on postural changes in respiratory function in these subjects. PURPOSE: The aim of this study was to investigate the postural changes in respiratory function and the presence of flow limitation (FL) and orthopnea in patients with nontoxic goiter. METHODS: In 32 patients with nontoxic goiter, respiratory function was studied in seated and supine position. Expiratory FL was assessed with the negative expiratory pressure method. Goiter-trachea radiologic relationships were arbitrarily classified as follows: grade 1, no evidence of tracheal deviation; grade 2, tracheal deviation present in lateral and/or anteroposterior plane but with tracheal compression < 20%; and grade 3, tracheal deviation present with compression > 20%. Subgroups were considered according to this classification and occurrence of orthopnea and FL. RESULTS: In all three groups of patients, the average maximal expiratory flow at 50% of FVC/maximal inspiratory flow at 50% of FVC ratios were > 1.1, suggesting the presence of upper airway obstruction. Grade 3 patients had a significantly lower expiratory reserve volume and maximal expiratory flow at 25% of FVC and higher airway resistance and 3-point FL score than patients with grade 1 and grade 2. The prevalence of orthopnea was highest in patients with grade 3 (75%, as compared to 18% in the grade 1 group). In patients with orthopnea, the prevalence of intrathoracic goiter was also higher (78%, vs 21% in patients without orthopnea). CONCLUSION: There is a high prevalence of orthopnea in patients with goiter, especially when the location is intrathoracic and causes a reduction of end-expiratory lung volume and flow reserve in the tidal volume range, promoting FL especially in supine position. Obesity is a factor that increases the risk of orthopnea in patients with goiter.